Valproate Levels Research Articles

Epilepsy and antiepileptic drugs: risk factors for atherosclerosis

Introduction: Epilepsy is a chronic disease that affects metabolism either alone or through the antiepileptic drug (AED) treatment. A risk of atherosclerosis has been found in epileptic patients. Aim: Prove the potential role of epilepsy and/or its treatment as atherosclerotic risk factors. Subject and Methods: Forty Egyptian patients with primary idiopathic epilepsy were compared to 20 healthy controls. B-mode ultrasound examination of the common carotid artery intima-media thickness (CCA IMT), measurement of serum lipid profile, fibrinogen and high sensitive C-reactive protein were performed to both groups. Results: Patients had significantly increased right and left CCA IMT (p < 0.05); elevated levels of HDL (p < 0.01) and hs-CRP (p = 0.009) in comparison to control subjects. Positive correlation was found between IMT and hs-CRP (p < 0.05) as well as fibrinogen level (p < 0.05). Carbamazepine level was positively correlated to triglycerides (r = 0.748, p = 0.013) and Valproate level was positively correlated to hs-CRP serum level (r = 0.556, p = 0.032). Conclusion: Epilepsy and AED's are potential risk factors for atherosclerosis. Weak relation between epilepsy and/or AED's and lipid profile was found. Hs-CRP may be implicated in atherosclerosis in epileptic patients.

Lack of Detectable Serum Levels Following Topical Fluoxetine Administration in a Child

[Author Affiliation]Dean Elbe. 1 Children's & Women's Mental Health Programs, BC Mental Health & Substance Use Services, Vancouver, British Columbia. 2 Department of Pharmacy, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia.Leslie Wicholas. 1 Children's & Women's Mental Health Programs, BC Mental Health & Substance Use Services, Vancouver, British Columbia. 3 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.Address correspondence to: Dean Elbe, PharmD, BCPP, Mental Health Building, P2-229, Children's & Women's Health Centre of British Columbia, Box 141-4500 Oak Street, Vancouver, BC, Canada V6H 3N1, E-mail: delbe@cw.bc.caTo the Editor:An 8-year-old boy with a history of attention-deficit/hyperactivity disorder (ADHD) combined subtype, complex partial epilepsy, pediatric migraine, nonverbal learning disorder, and anxiety disorder not otherwise specified was admitted to the inpatient child psychiatry unit of British Columbia's Children's Hospital in September 2012 for assessment and treatment. Admission medications included valproic acid (liquid) 250 mg twice daily, lisdexamfetamine 20 mg daily (dispersed in liquid), melatonin (sublingual) 5 mg at bedtime as needed, and fluoxetine 20 mg daily administered via topical application to alternating wrists every morning. The patient was extremely fearful of taking oral medications. This aversion developed after the family dog was euthanized. The patient feared that he would also die if he took oral medications. His parents had been restraining him and forcing him to take medically necessary oral medications, such as valproic acid for seizure prophylaxis.Upon learning of the topical fluoxetine prescription, the clinical pharmacist contacted the dispensing community pharmacy for details of the product. Topical fluoxetine had been dispensed since February 2012 for ∼7 months prior to admission. The product was compounded to contain fluoxetine 100 mg/mL in Lipoderm® , a proprietary permeation enhancer produced by the Pharmaceutical Compounding Centers of America.A literature search for data regarding topical absorption of fluoxetine in humans did not reveal any relevant articles. Data obtained from veterinary literature indicated that transdermal fluoxetine absorption was likely to be low (Ciribassi et al. 2003; Trepanier 2011). The patient's mother described a pattern of response consistent with what may be typically expected following administration of oral fluoxetine for treatment of anxiety, including a reduction in symptoms that was delayed in onset by 3-4 weeks following the start of topical fluoxetine administration. No adverse effects were reported. The clinical pharmacist recommended checking a serum fluoxetine level to assess whether any of the fluoxetine was reaching the systemic circulation. The patient was also very fearful of needles, and the family initially refused to consent to having bloodwork drawn. The patient's family did not want to stop topical fluoxetine administration, even following a conversation with the treating psychiatrist and clinical pharmacist about the likely low rate of transdermal absorption. Continued use of this product was considered to likely be ineffective for treatment of the patient's anxiety disorder, but very unlikely to be directly harmful to the patient.During the 1 month admission he was switched from liquid valproic acid to a divalproex sprinkle formulation (obtained via the Health Canada Special Access Program) which was consistently administered in hospital. With teaching and a rewards program implemented by unit staff, the patient became more amenable to taking medications orally. He no longer had to be restrained by his parents for medication administration. His parents consented to bloodwork to assess serum valproate and fluoxetine levels. …

Low-dose sodium valproate in the treatment of idiopathic generalized epilepsies

Most patients with idiopathic generalized epilepsies (IGEs) have good seizure control when on antiepileptic drugs. To analyze prospectively the response to low-dose sodium valproate (VPA) treatment (<1000 mg/day) together with plasma VPA levels in a cohort of patients with IGE. Patients with IGE were selected and followed for almost 2 years. In patients on VPA with no seizures in the last year, VPA dose was lowered to <1000 mg/day. Newly diagnosed patients with IGE started treatment on VPA directly on this low dose. Fifty-four patients were included, with juvenile myoclonic epilepsy (JME) in 23 (42.6%), juvenile absence epilepsy (JAE) in 17 (31.5%), and generalized tonic-clonic seizures only (GTCS only) in 14 (25.9%). VPA at low dose was administered to 38 (70%) patients. Mean plasma VPA level was 44.21 mg/l (18-78; SD 15.18). Seizure relapse during the 2-year follow-up was observed in 8 (21%). A reduction in adverse events was observed (P < 0.048). The only factor related to efficacy of VPA at low dose was syndromic diagnosis. Low-dose VPA controlled 92.9% (13) of patients with GTCS only, 78.3% (18) of those with JME, and 29.5% (5) of those with JAE. Low-dose VPA was a highly effective treatment for the majority of those with JME and GTCS only. The seizures in JAE tended to be more resistant to treatment, usually requiring higher doses of VPA or polytherapy.

Valproate induced hyperammonemic encephalopathy successfully treated with levocarnitine

Valproate-induced hyperammonemic encephalopathy is an unusual but serious adverse effect that is usually characterized by the acute onset of impaired consciousness, focal neurological symptoms and increased seizure frequency. It has been reported to occur at therapeutic valproate levels. We report a patient who developed valproate-induced hyperammonemic encephalopathy after a short treatment with valproate and was successfully treated with levocarnitine. We discuss this patient and review the literature regarding the use of levocarnitine in similar patients.

P86 – 1541 Prevalence of genetic polymorphisms of UGT1A6 and their association with serum valproate levels in north Indian children with epilepsy on valproate monotherapy

P86 – 1541 Prevalence of genetic polymorphisms of UGT1A6 and their association with serum valproate levels in north Indian children with epilepsy on valproate monotherapy

Risperidone, a risk factor for valproate-induced encephalopathy?

Valproate-induced encephalopathy (ViE) has been increasingly reported and several risk factors have been proposed. We report a case whereby a patient became encephalopathic while treated with valproate and upon initiation of risperidone. The underlying mechanism could be risperidone's interference with valproate's binding to albumin, raising free valproate levels, which would impair the urea cycle and reduce ammonia conversion, leading to a hyperammonemic encephalopathy. The present case suggests a causal link, although further studies will be necessary to establish this. Nevertheless, clinicians should be aware of this possible interaction and consider carefully before concomitant administration of valproate and risperidone, mainly in patients with other risk factors for ViE, so this complication can be avoid or promptly diagnosed and treated.

2764 – Valproic acid induced hyperammonemic encephalopathy: report of one case

Valproate (VPA) is widely used for acute and maintenance therapy of bipolar disease and it is the most prescribed drug for epilepsy treatment worldwide. VPA-induced hyperammonemia is a serious and unusual advers effect of VPA treatment. We aimed to describe the 20 year-old-woman bipolar case of VPA induced hyperammonemic encephalopaty with therapeutic VPA levels and normal liver functions. The case will be discussed. The patient complained of confusion, disorientation, somnolance, agitation and slurred speech at the end of the first week of VPA treatment. VPA blood level was 116.5 μg/mL (N:50-125) and ammonia level was 237 μmol/L (N:10-50). Other laboratory tests including serum transaminases (both ALT and AST) and coagulation profile (PT, PTT and INR) were normal. After discontinuation of VPA treatment and hydration, these symptoms have disappeared dramatically. After 24 hours, blood ammonia level was 80 μmol/L and patient returned the baseline mental status. Hyperammonemia occurs due to inhibition of mitochondrial enzymes in the urea cycle by valproic acid. Hyperammonemia and encephalopathy can develop even at therapeutic concentrations without elevated liver function enzymes. Clinicians should be aware that VPA- induced hyperammonemia and encephalopathy is still one of the most feared side effects of VPA which may require emergent management.

Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid

Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.

Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012

Valproate (VPA) is a medication that is widely used in the treatment of neurological and psychiatric disorders, such as epilepsy and bipolar disorder. Valproate-induced hyperammonemic encephalopathy (VHE) is a rare central nervous system adverse effect of this medication that is characterized by impaired consciousness, which can range from drowsiness to coma; increased seizure frequency; acute cognitive symptoms; and gastrointestinal symptoms. In this manuscript, we report a single case and also review previous cases of VHE (n=20) in Chinese patients to identify risk factors for VHE. Increasing clinicians’ awareness of VHE during concomitant VPA therapy is of utmost importance. Serum ammonia level is a useful and important diagnostic test. The discontinuation of VPA is currently the mainstay of treatment for VHE.

A Case of Valproate Toxicity Related to Isoniazid

A Case of Valproate Toxicity Related to Isoniazid

Rapid Reversal of Corticosteroid-Induced Mania with Sodium Valproate: A Case Series of 20 Patients

Glucocorticoids are widely used in medicine and are known to cause psychiatric side effects, including mania. There is anecdotal evidence that sodium valproate is effective for treating psychiatric side effects of glucocorticoids. To describe a case series of 20 patients receiving corticosteroids for various medical conditions who developed manic-like symptoms. They were treated with sodium valproate while continuing on corticosteroids. Patients treated with corticosteroids who reported to their physician subjective distress or who were openly disruptive in the ward were assessed by a consultation-liaison psychiatrist on the same day with the Young Mania Rating Scale. Immediately afterwards, blood was taken to measure the cortisol or dexamethasone level and then started on sodium valproate 500 mg twice daily. Valproate levels were measured on day 3 to adjust the dose. There was a significant, rapid improvement of symptoms within 48 hours after sodium valproate was initiated. Within 72 hours all patients were euthymic and remained so over the ensuing week. The only major side effect was hyperammonemia in 1 case which resolved when valproate was stopped. This case series shows that sodium valproate is a safe medication that rapidly reverses manic-like symptoms within a few days without needing to stop the corticosteroids, thus allowing the medical treatment to continue. The ability to continue treatment while controlling or ameliorating the psychiatric side effects of glucocorticoids with sodium valproate is an advance over previous approaches. The mechanism of this rapid action is unclear and deserves further study.

1527 Seizure Worsening Caused by Low Serum Valproate Levels from an Interaction between Valproate and Meropenem

BackgroundMeropenem is a carbapenem antibiotic, has a broad spectrum of antimicrobial activity. Valproate is widely used in the treatment of epileptic seizures in children. In last years, low serum concentrations...

“Hyperammonemia” - A Look Beyond the Liver

Purpose: A 51-year-old female with history of seizure disorder and stroke presented with decreased level of consciousness and lethargy of one day duration. She did not have other symptoms of neurologic or liver disease. On examination, the patient was drowsy but responsive. Her vital signs and rest of the physical examination was normal except residual weakness in left upper extremity from her previous stroke. The patient had no signs of jaundice and no stigmata of chronic liver disease. Seizures had been well controlled with valproate. Complete blood count, electrolytes, creatinine, liver biochemistry, international normalized ratio and albumin, were normal. The results of a toxicology screen and a head CT scan were unremarkable. The patient's serum valproate level was 77.4 mcg/ml, which was within the therapeutic range (50-120 mcg/ml). An electroencephalogram showed diffuse slowing of background activity consistent with metabolic encephalopathy. Subsequent tests revealed an elevated ammonia level 195 mmol/l (3-37). Her liver biochemistry was normal; thus, valproate-related hyperammonemic encephalopathy (VHE) was suspected. To support the diagnosis, carnitine levels were checked. Her free carnitine level was 4 μMol/l (25-60) and total carnitine level was 9 μMol/l (34-86) both of which were low. Valproate therapy was immediately discontinued, and was started on treatment with L-Carnitine. Over the next week, the patient's level of consciousness and ammonia level returned to normal. Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. VHE is characterized by a decreasing level of consciousness, vomiting, and lethargy. Several mechanisms have been postulated to cause hyperammonemia; 1) Propionate, a metabolite of valproate reduces carbamoyl phosphate synthetase 1 activity results in accumulation of ammonia. 2) Reduction of hepatic carnitine levels by valproate which disrupts the urea cycle resulting in ammonia accumulation. Treatment with carnitine supplements can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. In our patient, there was a good correlation between the fall in serum ammonia levels (after VPA withdrawal) and clinical improvement confirming our diagnosis of Valproate induced hyperammonemic encephalopathy. Conclusion: We often attribute encephalopathy and elevated levels of serum ammonia to liver failure. However, other conditions, including valproate-related hyperammonemic encephalopathy, must be considered. In our case, the clues to the correct diagnosis were the patient's normal hepatic synthetic function and the use of valproate therapy.

A Severe Valproate Overdose With Complete Recovery in a Newborn

Valproate overdose, extensively described in adults and older children, has been reported in only 1 newborn: a 26-day-old female who developed a severe cerebral edema leading to a fatal outcome. Therefore, the consequences of valproate overdose are largely unknown in the neonatal period. Here, we present the clinical evolution of a 6-day-old newborn who developed hyperammonemic encephalopathy after the accidental administration of 310 mg/kg of oral valproate in a single dose. Despite the very high valproate and blood ammonia levels, he did not develop life-threatening complications and he completely recovered without sequels. His brain magnetic resonance imaging showed symmetric focal T1 prolonged signals in both globi pallidi that completely resolved over time, a neuroimaging pattern that was not previously described in valproate overdose. Our case report suggests that valproate overdose in newborns can be completely reversible even when the valproate and ammonium blood levels are very high.

Cardiac arrest in pregnancy: lessons to be learned!

Dear Editor, Cardiac arrest in pregnancy is a rare event with an incidence of 1 per 30,000 pregnancies in western countries. However, it is important for emergency physicians to be familiar with the indications for performing a perimortem caesarean section (PMCS). We report two cases of PMCS performed during cardiopulmonary resuscitation (CPR). The first case, a 37-year-old female, G1P0, had a medical history of epilepsy. Her pregnancy was complicated at 30 weeks gestation by a single uncomplicated grand mal seizure as a result of low valproate level. She was admitted, at 35 weeks gestation, for pregnancy-induced hypertension. Laboratory results were normal. Two days after admission she was found unresponsive. She had pulseless electrical activity (PEA) and hypoxia due to an epileptic insult was considered the diagnosis. She was treated according to the advanced cardiac life support protocol. Fifteen min after the start of CPR a PMCS was performed. There was an immediate return of spontaneous circulation (ROSC). Unfortunately 2 days later her treatment had to be withdrawn, because of poor neurological prognosis. The male infant (2,300 g; Apgar score 0/6/7) had seizures and was resuscitated. The baby survived, and follow-up 12 months after delivery showed normal growth and slight neurologic development impairment. The second case, a 35-year-old female, G3P1, had an uneventful medical history and was admitted for induction of labour at 41 weeks and 3 days gestation. After spontaneous rupture of membranes the patient suffered from dyspnoea, hypotension, bradycardia, and cyanosis. Supplemental oxygen and left lateral tilt position did not alleviate the symptoms. Upon arrival of the resuscitation team the patient had PEA. Amniotic fluid embolism was considered the diagnosis. Perimortem caesarean section was performed in the delivery room after 4 min, resulting in the immediate ROSC and the birth of a girl (3,450 g; Apgar score 2/6/7). Both were discharged without abnormalities. During CPR in late pregnancy the patient should be positioned in left lateral tilt to alleviate aortocaval compression [1]. If sufficient cardiac output is not achieved within 4 min after cardiac arrest, in a pregnancy of more than 20 weeks gestation, PMCS must be considered [1]. In our cases an important observation was made that immediately after delivery of the infant there was a ROSC, indicating that indeed pooling of blood in the uterus and placenta as well as aortocaval compression played a pivotal role in the prior unsuccessful resuscitation. We performed two PMCS in our hospital. The first PMCS was before the courses based on the Managing Obstetric Emergencies and Trauma (MOET) principles were given at our institution [2, 3]. Important differences between the first and second case were the immediate awareness of the necessity to perform PMCS in the first 4 min after persistent cardiopulmonary arrest, the availability of an emergency PMCS box [4] in the delivery room and the notion to perform the PMCS on the spot. This all resulted in a much faster delivery of the baby and more importantly much faster return of the maternal circulation, resulting in favourable clinical outcome for both mother and child.

Unilateral tremor induced by risperidone in a patient with acute mania: Vitamin B12 deficiency as possible mediating factor

Identification and management of drug-induced movement disorders is a clinical challenge, more so when the clinical presentation is atypical. A young male with acute mania was under treatment with sodium valproate and risperidone. He developed tremors of right hand and neck. These were present at rest and exacerbated by mental activity, when under observation and during voluntarily initiated activity. There were no associated extra pyramidal symptoms or cerebellar signs. Investigations for other common causes of tremors did not reveal any evidence except for low value of serum vitamin B12 levels. The tremors persisted after the withdrawal of valproate, but resolved following the withdrawal of risperidone. It is a common dictum that drug-induced tremors are bilateral. This may not be true always as we found out in our case. These movements were probably induced by risperidone. This atypical presentation could be due to concurrent use of valproate and low serum vitamin B12 levels.

Rare Magnetic Resonance Imaging Findings in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

A 3-year-old boy receiving valproate for 1.5 months presented with sudden-onset unprovoked seizures and unconsciousness. Hypoketotic hypoglycemia, hyperammonemia, and deranged liver function were detected. Elevated medium-chain urinary acylglycines and plasma acylcarnitine were detected. His serum valproate level was elevated. Valproate toxicity had been precipitated in presence of medium-chain acyl-CoA dehydrogenase deficiency. Cranial magnetic resonance imaging brain indicated unilateral basal ganglia ischemia instead of the bilateral changes expected in metabolic disease.

Sodium valproate induced hyperammonaemia in an elderly patient with affective disorder

A 60 year old patient with bipolar affective disorder presented with clinical features suggestive of encephalopathy two weeks after commencing treatment with sodium valproate. He developed sudden onset alteration of sleep pattern, extreme agitation and hallucinations. He was disoriented in time, place, and person. Serum valproate level was within the therapeutic range. SGOT, SGPT, serum creatinine and echocardiogram were normal. Serum ammonia level which was 90 μg/dl (range: 25 - 80 μg/dl) at the time of admission had risen to 180 μg /dl on the 3rd day of hospital stay. Rapid clinical recovery from encephalopathy resulted a few days after withholding sodium valproate. DOI: http://dx.doi.org/10.4038/sljpsyc.v2i1.3164 SL J Psychiatry 2011; 2 (1): 31-32

The Effect of Lamotrigine on Valproic Acid Concentrations

To determine whether lamotrigine affects serum concentrations of valproic acid. Pre-morning-dose serum valproic acid concentrations were measured in 76 subjects with epilepsy (48 M, 28 F, age range 6-20 years, mean age 14 years) in whom lamotrigine was added while the dose of valproate and other medication remained unchanged. In a comparison group, either acetazolamide or gabapentin was added to sodium valproate. Far more subjects (26/76 = 34%) had an increase of >25% in valproic acid concentration with lamotrigine than those who had a decrease of >25% (4/76 = 5.3%). The mean valproic acid concentration before starting lamotrigine was 61.0 mg/L and on lamotrigine was 67.1 mg/L; the difference in means was 6.1 mg/L (standard error 2.1, 95% confidence limits 2.0, 10.2, p=0.004, highly significant, paired sample t-test, two-tailed), a rise of 10%. The change in valproic acid concentration appeared to depend on the initial valproic acid concentration (Pearson r=-0.405, p<0.001). In 14.5% of the subjects the increase in valproate concentration was >50%, which could lead to toxicity, although the increase tended to occur with lower or intermediate initial valproic acid concentrations whereas a small overall decrease in valproic acid concentrations with lamotrigine was found with the higher initial valproic acid concentrations. One subject had abnormal bruising with the increased valproate level after lamotrigine was added, which resolved on decreasing the valproate dose. The changes in valproic acid concentrations in the comparison group were small (mean increase 2.6%) and were not statistically significant. Although there is a wide variation in the changes of valproic acid concentrations when lamotrigine is added, the concentrations tend to increase rather than decrease, especially with low or intermediate initial valproic acid concentrations. In some cases valproate toxicity, manifested by abnormal bruising, may result, although at higher initial valproic acid concentrations the valproic acid concentration usually tends to fall slightly with the addition of lamotrigine.

Effectiveness of hemodialysis in a case of severe valproate overdose

A case of severe sodium valproate overdose is presented in which medicinal management failed to reverse coma of the patient. High-flux hemodialysis was then used to eliminate sodium valproate. This case demonstrated the effectiveness of hemodialysis in not only decreasing valproate levels very rapidly but also as an effective anti-coma management.